Gender difference is a risk factor for abdominal aortic aneurism formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor influence the male gender difference, indicating that androgen receptor signaling may affect abdominal aortic aneurism development. Using angiotensin II induced abdominal aortic aneurism in apolipoprotein E null mouse models (82.4% abdominal aortic aneurism incidence), we found that mice lacking androgen receptor failed to develop abdominal aortic aneurism and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that androgen receptor expression in endothelial cells, macrophages or smooth muscle cells might play a role in abdominal aortic aneurism development. Selective knockout of androgen receptor in each of these cell types further demonstrated that mice lacking androgen receptor in macrophages (20% abdominal aortic aneurism incidence) or smooth muscle cells (12.5% abdominal aortic aneurism incidence), but not in endothelial cells (71.4% abdominal aortic aneurism incidence) had suppressed abdominal aortic aneurism development. Mechanism dissection showed that androgen receptor functioned through modulation of interleukin 1α and transforming growth factor β1 signals and by targeting androgen receptor with androgen receptor degradation enhancer ASC-J9® led to significant suppression of abdominal aortic aneurism development. These results demonstrate the underlying mechanism by which androgen receptor influences abdominal aortic aneurism development through interleukin 1α and transforming growth factor β1, and provides a potential new therapy to suppress/prevent abdominal aortic aneurism by targeting androgen receptor with ASC-J9®.
There has been an increased demand for 3G cell phones that support multiple bands of operation and are backward compatible with the 2G/2.5G standard to provide coverage where 3G networks have not yet been fully deployed. The transceiver design for such a handset becomes complicated with the need for separate transceivers for 3G and 2G/2.5G [1,2] or for multiple inter-stage receive / transmit SAW filters [3]. A single-chip transceiver that operates as a multimode multiband radio and eliminates the inter-stage receive / transmit SAW filters is presented. Figure 6.3.1 shows the block diagram of the transceiver with 7 primary and 4 diversity bands in WCDMA, and quad band in GSM. The transceiver is designed to operate in any of the UTRA bands 1 to 10, with the exception of band 7. It supports HSDPA (Cat 1-12), HSUPA (Cat 1-6), EGPRS (Classes 1-12, 30-39), and compressed mode of EGPRS / WCDMA operation. The transceiver is compliant with 3G DigRF interface 3.09.The analog / RF section of the transmitter is shown in Fig. 6.3.2. The I/Q DAC is based on oversampled current steering with 10b accuracy realized with a 6b-unary and 4b-binary segmentation. The output of the DAC is fed to a 3 rdorder Chebyshev continuous-time filter that attenuates out-of-band noise and DAC images and drives the I/Q modulator. The filter can be configured to operate in WCDMA, GMSK or EDGE mode. The I/Q modulator is a passive LO-2LO mixer. Two levels of passive switches are driven by LO and 2×LO frequencies with proper phases. This mixer configuration achieves both lower phase noise in the LO path and isolation between I and Q baseband inputs, and addresses the stringent linearity and noise requirements of GSM/WCDMA. The differential output of the I/Q modulator is converted to single-ended output using an on-chip balun. The balun output is then amplified in the driver stage and sent off-chip to the PA. The transmitter provides 80dB of gain-control range in WCDMA mode and 40dB in EDGE mode. The gain control is distributed across the chain and designed to meet the linearity and noise requirements over power-control range, while optimizing the current consumption. At high power (24 to 0dBm) a closed-loop power control scheme in the transceiver is used for accurate power control, and at lower power (0 to -57dBm) a conventional power-control scheme through the base-station is used.The architecture of the receiver front-end is shown in Fig. 6.3.3. The mixers and LO buffers are shared among several LNAs to reduce die area. The mixer outputs are connected to the virtual grounds created by the transimpedance amplifiers (TIAs) and its inputs are driven by the output current from the LNA. In this current-driven passive-mixer topology, the voltage swings at the mixer input and output are significantly reduced, resulting in improved linearity. In a passive mixer design, the noise contribution of the TIA increases as the impedance at the mixer input decreases. Therefore, an LC tank is used at the LNA cascode output with switchable capacitors to adjust the tan...
The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant–syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDm through K14-Cre–mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9). CyldEΔ9/Δ9 mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c–Myc (S62) were markedly elevated in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome.
Cell-based mathematical models have previously been developed to simulate the immune system in response to pathogens. Mathematical modeling papers which study the human immune response to pathogens have predicted concentrations of a variety of cells, including activated and resting macrophages, plasma cells, and antibodies. This study aims to create a comprehensive mathematical model that can predict cytokine levels in response to a gram-positive bacterium, S. aureus by coupling previous models. To accomplish this, the cytokines Tumor Necrosis Factor Alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 10 (IL-10) are included to quantify the relationship between cytokine release from macrophages and the concentration of the pathogen, S. aureus, ex vivo. Partial differential equations (PDEs) are used to model cellular response and ordinary differential equations (ODEs) are used to model cytokine response, and interactions between both components produce a more robust and more complete systems-level understanding of immune activation. In the coupled cellular and cytokine model outlined in this paper, a low concentration of S. aureus is used to stimulate the measured cellular response and cytokine expression. Results show that our cellular activation and cytokine expression model characterizing septic conditions can predict ex vivo mechanisms in response to gram-negative and gram-positive bacteria. Our simulations provide new insights into how the human immune system responds to infections from different pathogens. Novel applications of these insights help in the development of more powerful tools and protocols in infection biology.
-This paper presents an integrated wide-range VCO with a modified tuning scheme to deal with VCO frequency drift over temperature. In this approach, during the coarse-tune operation, VCO tune voltage is a function of temperature such that it resembles the inverse function of VCO fine-tune characteristic. Without degrading VCO performance, the proposed temperature adaptive tuning optimizes the maximum tolerable VCO temperature frequency drift over which PLL remains locked. As a result, VCO gain can be reduced significantly, making VCO less sensitive to PLL tune voltage noise. Integrated in a multistandard multi-band transceiver with a small VCO gain of 50MHz/V at 3.90GHz, PLL remains locked despite 45MHz frequency drift of VCO over [-30ºC, 85ºC]. Using an on-chip inductor, VCO covers from 3.15GHz to 4.60GHz, achieving -138.0dBc/Hz phase noise at 3.0MHz at 3.90GHz by drawing just 8.5mA from 1.60V supply in 0.13u CMOS process.Index Terms -Wide-range VCO, VCO temperature frequency drift, VCO fine-tune , on-chip inductor, PLL
In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7–10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10–75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.
Abstract:The high resolution of the latest high-performance mobile display devices has resulted in an increase in the main frame buffer size and related bandwidth, and this is one of the main causes of a reduced battery life. As a means to solve this problem, one-dimensional line-based compression methods have been studies in order to be implemented in the limited chip design environment of the mobile display driver ICs. Conventional lossless compression techniques do not have a high compression ratio enough for complex images to ensure a sufficient power reduction. On the other hand, a wavelet-based 1D SPIHT method has been studied for use as a lossy-compression method with a high compression ratio while keeping the image quality. However, this method requires large hardware resources due to the performance for iterative calculations and sorting process. This paper proposes a novel wavelet-based lossy compression system that can achieve high compression and image quality while maintaining low complexity. The Frequency Adaptive Line Compression composed of 4-level DWT, horizontal predictive coding for the low-frequency regions, frequency selective zerozone quantization for high-frequency regions, and frequency component entropy coding. Experimental results confirmed that the proposed technique could achieve a higher compression ratio than the one required of conventional lossless compression methods and could also be implemented with a significantly less complexity than the conventional SPIHT method at the same compression ratio.
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